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Example clinical scenario

A nine-month-old girl is referred to the paediatric clinic by her GP because of short stature, relatively small head size, multiple café-au-lait macules and a smaller left thumb. She was born small for gestational age. Development to date has been normal.

When to consider genomic testing

You should consider investigating for Fanconi anaemia if a child presents with any of the clinical features listed below.

  • Physical characteristics:
    • Prenatal and/or postnatal short stature with or without microcephaly.
    • Unusual skin pigmentation (such as multiple café-au-lait macules, generalised hyperpigmentation or areas of hypopigmentation).
    • Unilateral or bilateral limb skeletal anomalies (commonly radial ray anomalies such as absent, hypoplastic or bifid thumbs and hypoplastic or absent radii).
    • Genitourinary anomalies (such as horseshoe or ectopic kidney, hypospadias or bicornuate uterus).
    • Endocrine disorders (such as hypothyroidism or impaired glucose tolerance).
    • Ophthalmic anomalies (such as microphthalmia, cataracts or strabismus).
    • Less commonly: Congenital heart disease, hearing loss, gastrointestinal anomalies, developmental delay or intellectual disability (around 10% of cases).
  • Clinical or haematological suggestion of bone marrow impairment (the average age of onset is seven to eight years), including:
    • thrombocytopenia: Presenting with easy bruising, petechiae and/or nose bleeds;
    • leukopenia: Either presenting with recurrent infections or presenting incidentally on full blood count; and/or
    • anaemia: May be preceded by increased fetal haemoglobin, pallor and/or fatigue.
  • Early onset malignancies (more commonly found from adolescence onwards):
    • acute myelogenous leukaemia; and/or
    • solid tumours (head and neck squamous cell carcinoma, skin, genitourinary).

What do you need to do?

  • Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
  • Decide which of the panels best suits the needs of your patient or family:
    • R260 Fanconi anaemia or Bloom syndrome (chromosome breakage testing): Should be undertaken if there is a strong suspicion of Fanconi anaemia or Bloom syndrome (this is not a genomic sequencing test but instead looks for DNA repair defects);
    • R229 Confirmed Fanconi anaemia or Bloom syndrome (mutation testing): Should be undertaken if chromosome breakage analysis supports the diagnosis of Fanconi anaemia and molecular confirmation is required (this test comprises gene panel sequencing and multiplex ligation-dependent probe amplification (MLPA) for a small number of genes known to cause Fanconi anaemia);
    • R258 Cytopenia (Fanconi breakage testing indicated): Should be considered if the main findings are recurrent infections with persistent or recurrent (analysis includes both DNA repair testing and sequencing and MLPA analysis of a panel of associated genes); or
    • R27 Paediatric disorders: If there is developmental delay or intellectual disability in association with congenital malformation or overgrowth, and you would like to investigate chromosomal and single-gene causes. This test includes microarray and a whole genome sequencing (WGS) ‘super panel’ (a panel comprised of several different constituent panels forming one large panel).
    • For tests that are undertaken using WGS, including R27, you will need to:
    • For tests that do not include WGS, including R260, R229 and R258:
      • you can use your local Genomic Laboratory Hub test order and consent (RoD) forms; and
      • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
    • The majority of tests are DNA-based, and an EDTA sample (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (green-topped tube).
    • R27 is a large WGS ‘super panel’ that currently requires authorisation from clinical genetics to request.
  • Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.
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  • Last reviewed: 24/03/2023
  • Next review due: 24/03/2024
  • Authors: Dr Eleanor Hay
  • Reviewers: Dr Amy Frost, Dr Emile Hendriks